PPAR is known as one of the nuclear receptor families and is known to have three subtypes (alpha, gamma, and delta) (Nature, 347, 645-650, 1990; Cell, 68, pp 879-887, 1992; Cell, 97, pp 161-163, 1999; Biochim. Biophys. Acta., 1302, pp 93-109, 1996; and Journal of Medicinal Chemistry, 43, pp 527-550, 2000). Each receptor appears to modulate pathways at the interface between intermediary metabolism and inflammation, making them physiologically and clinically relevant (Nature 454, 470-477, 2008). Therefore, PPARs are targets of drugs in use and in development to treat disease, and they modulate metabolic and inflammatory pathways by responding to nutritional signals through ligand activation of transcription.
PPARα is activated by fibrate drugs to lower triglycerides and raise HDL (Arterioscler Thromb Vasc Biol 28, 39-46, 2008). PPARγ is targeted by glitazones to treat diabetes (N Engl J Med 351, 1106-1118, 2004), and pharmacological activation of PPARδ appears to improve several metabolic parameters in humans (Diabetes 57, 332-339, 2008). PPARs are ligand-activated receptors that heterodimerize with RXR, bind to response elements in target genes, and alter co-activator/co-repressor dynamics to induce transcription. Fatty acids, especially polyunsaturated ones, are thought to be preferred PPAR ligands, but a wide variety of lipids (Proc Natl Acad Sci USA 94, 4312-4317, 1997; Proc Natl Acad Sci USA 94, 4318-4323, 1997; Mol Endocrinol 11, 779-791, 1997; J Biol Chem 270, 23975-23983, 1995) have been implicated in PPAR activation including saturated fatty acids, fatty acyl-CoA species, eicosanoids (including prostaglandins, leukotrienes, and HETEs), oxidized fatty acids, and oxidized phospholipids. PPARα is activated by drugs to treat human disorders of lipid metabolism (WO 2006-006832, U.S. Pat. No. 7,301,033, European Journal of Clinical Investigation, 34, 429-435, 2004). Of the three subtypes of PPAR, PPARα is mainly expressed at high levels in liver where it promotes fatty acid oxidation, ketogenesis, lipid transport, and gluconeogenesis (Nat Med 9, pp. 1069-1075, 2003; Annu Rev Nutr 21, pp. 193-230, 2001).
Even though some naturally occurring fatty acids such as pristanic acid, phytanic acid, palmitic acid, oleic acid, linoleic acid, and arachidonic acid have been characterized as endogenous ligands of PPARα, it has been reported that some of these naturally occurring free fatty acids which act as ligands of PPARα do not bind with sufficient affinity to PPARα in comparison to a prototypical synthetic fibrate agonist, Wy14,643, within the context of alcohol-induced fatty liver disease. (Journal of Lipid Research, 41(11) 1801-1807, 2000; Molecular Endocrinology 11, 779-791, 1997; European Journal of Clinical Investigation, 34, 429-435, 2004; Journal of Biological Chemistry, 278 (30), 27997-28004, 2003.) Moreover, none of these naturally occurring free fatty acids are authentic endogenous PPARα ligands because they do not occupy the nuclear receptor binding site in vivo while the receptor is actively driving transcription. Therefore, such free fatty acids are not the most physiologically relevant tissue-specific endogenous PPARα ligands. Furthermore, to date, a physiologically relevant and naturally occurring endogenous tissue-specific phosphatidylcholine ligand that selectively binds to PPARα has not been disclosed as a treatment for fatty liver disease.
Fatty liver disease is one of the most common causes of chronic liver disorders. (Journal of Gastroenterology and Hepatology, 23, 102-109, 2006.) Although the pathogenesis of human fatty liver disease is not completely understood, it is generally acknowledged that the disease status is potentiated by an increased influx and accumulation of free fatty acids in the liver. (European Journal of Clinical Investigation, 34, 429-435, 2004.) The increased fatty acid input to the liver is counterbalanced with fatty acid oxidation systems to prevent fat accumulation and PPARα may play a key role in this step by controlling fatty acid oxidation in all potential sources. (European Journal of Clinical Investigation, 34, 429-435, 2004). U.S. Pat. No. 7,442,796 discloses that a substantial fraction of the population is affected by fatty liver disease, also known as nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic steatohepatitis (NASH). NASH is often associated with obesity and diabetes. Fatty liver disease or hepatic steatosis, the presence of droplets of triglycerides with hepatocytes, predisposes the liver to chronic inflammation (detected in biopsy samples as infiltration of inflammatory leukocytes), which can lead to fibrosis and cirrhosis. Fatty liver disease is generally detected by observation of elevated serum levels of liver-specific enzymes such as the transaminases ALT and AST, which serve as indices of hepatocyte injury, as well as by presentation of symptoms which include fatigue and pain in the region of the liver, though definitive diagnosis often requires a biopsy. Hepatic gene expression profile encompassing PPARα and some representative enzymes involved in the oxidation of free fatty acids like acyl-CoA oxidase(ACO or AOX); acyl-CoA dehydrogenase, Carnitine Palmitoyl Transferase I and II(CPT-1 and CPT-II), Fatty Acid Binding Protein, Fatty Acid Transport Protein have been reported as being potentially involved in the pathology of fatty liver disease. (Journal of Gastroenterology and Hepatology, 23, 102-109, 2006; European Journal of Clinical Investigation, 34, 429-435, 2004; Journal of Biological Chemistry, 278 (30), 27997-28004, 2003.)
Although PPARα agonists are relatively effective in treating nonalcoholic fatty liver disease, there is still an on-going need for safe and effective treatments for fatty liver disease. (Journal of Gastroenterology and Hepatology, 23, 102-109, 2006; U.S. Pat. No. 7,442,796.) Therefore, treatment of fatty liver disease using a tissue specific naturally occurring authentic endogenous ligand of PPARα would be of value in treating this condition. Furthermore, it is anticipated that amongst other benefits, the delivery of a therapeutically effective PPARα-ligand will eventually lead to the reduction in liver inflammation and fat content, resulting in attenuation, halting, or reversal of the progression of NASH toward fibrosis and cirrhosis.